ES2368788T3 - PROCEDURE TO PREPARE DERIVATIVES OF PIPERAZINA AZAINDOLOXOACETICA REPLACED WITH TRIAZOL AND NEW SALIN FORMS PRODUCED IN THE SAME. - Google Patents

Abstract

A process for preparing compound L, which has the structure comprising subjecting compound H of the structure to a Grignard acylation reaction when acid chloride 1 is reacted with compound H to form compound L. in which The Grignard acylation reaction is carried out in the presence of C2H5MgCl in an organic solvent, 2- CH3THF and an organic base, in which the Grignard acylation reaction is carried out at a temperature in the range of about -50 to about 25 ° C. and wherein in compounds L and H, R 2 is F, R 3 is H and R 18 is H or alkyl.

Description

Procedure for preparing triazole-substituted azaindole-monoacetic piperazine derivatives and new salt forms produced therein

The present application claims priority over the provisional US application No. 60 / 693,004 filed 5 on June 22, 2005.

Field of the Invention

The present invention relates to a process for preparing triazole substituted azaindoloxoacetic piperazine derivatives, to new intermediates produced therein, to new N-1 and amorphous crystalline forms of a 1,2,3-triazole substituted azaindoloxoacetic piperzine derivative and procedures to produce these new

10 ways

Background of the invention

U.S. Patent Application No. 10 / 969,675 filed on October 20, 2004 by Tao Wang et al. (President's file GY0085B CNT1) discloses substituted azaindoloxoacetic piperazine derivatives that are antiviral agents, particularly HIV inhibitors having the formula

in which: Q is selected from the group consisting of:

R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen, halogen, cyano,

20 nitro, COOR56, XR57, C (O) R7, C (O) NR55R56, B, D and E with the proviso that at least one of R1-R4 is selected from B or E; in which - - represents a carbon-carbon bond or does not exist;

m is 1 or 2;

R5 is hydrogen or (CH2) nCH3, -C (O) (CH2) nCH3, -C (O) O (CH2) nCH3, -C (O) (CH2) nN (CH3) 2, where n is 0 -5;

R6 is O or does not exist;

A is selected from the group consisting of C1-6 alkoxy, aryl and heteroaryl; wherein said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl; and said aryl or heteroaryl is optionally substituted with one or two same or different members selected from the group consisting of amino,

Nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl; -W- is

B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroarylcyclic, S (O) 2R8, C (O) R7, XR8a, alkyl (C1-6 ) NR40R41, (C1-6) alkyl COOR8b; wherein said aryl, heteroaryl and heteroarylcyclic are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group F; wherein the aryl is naphthyl or substituted phenyl; wherein the heteroaryl is a mono or bicyclic system containing 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein heteroaryl cyclic is a 3 to 7 membered monocyclic ring that may contain 1 to 2 heteroatoms in the ring structure and that may be fused to a benzene or pyridine ring;

q is 0, 1 or 2;

D is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56 , hydroxy, cyano and XR57;

E is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57, SO2-C1-6 alkyl and SO2Ph; wherein the heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms;

F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen , nitro, -C (O) R57, benzyl, NR42C (O) -alkyl (C1-6), -NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) heteroalicyclic, a cyclic N-lactam of 4, 5 or 6-membered ring, -NR42S (O) 2-alkyl (C1-6), -NR42S (O) 2 -cycloalkyl (C3-6) , -NR42S (O) 2-aryl, -NR42S (O) 2-heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-C 1-6 alkyl, S (O) 2-aryl, -S ( O) 2NR42R43 NR42R43, (C1-6) -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, (C1-6) -NR42R43 alkyl , COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O ) R57, benzyl, -NR48C (O) -alkyl (C1-6), NR48C (O) -cycloalkyl (C3-6), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O ) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-C 1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), -NR48S ( O) 2-aryl, NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, alkyl (C1-6) C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54, alkyl (C1-6) -NR48R49, COOR54 and alkyl (C1-6) -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R7 is selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with one to three same or different substituents selected from the group F; in which for R7, R8, R8a,

R8b

aryl is phenyl; heteroaryl a mono or bicyclic system containing 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic ring system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five equal substituents

or different selected from group F;

R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens or one to five same or different substituents selected from the group F;

R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

each of R9, R10, R11, R12, R13, R14, R15, R16 is independently selected from the group consisting of hydrogen and (C1-6) alkyl; wherein said (C1-6) alkyl is optionally substituted with one to three same or different halogens;

X is selected from the group consisting of NH or NCH3, O and S;

R40 and R41 are independently selected from the group consisting of

(a) hydrogen;

(b)

 (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to 5 two same or different substituents selected from the group F; Y

(c) (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic;

or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and in which said aryl; heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; wherein for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; with the proviso that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or

15 (b);

R42

 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, alkoxy

20 (C1-6), cycloalkyl (C3-7), aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group G; wherein for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; Heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and

25 morpholine;

each of Ra and Rb are independently H, (C1-6) alkyl or phenyl;

R46 is selected from the group consisting of H, OR57, and NR55R56;

R47 is selected from the group consisting of H, amino, halogen, phenyl and (C1-6) alkyl;

R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

R50 is selected from the group consisting of H, (C1-6) alkyl, (C3-6) cycloalkyl and benzyl; wherein each of said alkyl (C1-6), cycloalkyl (C3-7) and benzyl are optionally substituted with one to three same or different halogens, amino, OH, CN or NO2;

R54 is selected from the group consisting of hydrogen and (C1-6) alkyl;

R54 'is (C1-6) alkyl;

R55 and R56 are independently selected from the group consisting of hydrogen and (C1-6) alkyl; Y

R57 is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl.

Among the total of 350 compounds disclosed in the application serial number. 10 / 969,675 are the 1,2,4-triazole derivatives of the structure

40 (hereinafter Compound I,

or derivative of I 1,2,4-triazole

or compound I of 1,2,4-triazole) disclosed in Example 316, and the 1,2,3-triazole derivative of the structure

5 (hereinafter Compound II,

or derivative II of 1,2,3-triazole

or compound II of 1,2,3-triazole) disclosed in Example 216.

Summary Description of the Invention

In accordance with the present invention there is provided a process for preparing compound IIA having the structure

wherein A is selected from C1-6 alkoxy, aryl and heteroaryl; wherein aryl is phenyl or naphthyl; the heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl and

Benzothiazolyl; and the aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from amino, nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl;

R18 is H or alkyl;

R2 and R3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, C (O) R7, C (O) NR55R56, B, D and E;

B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroarylcyclic, S (O) 2R8, C (O) R7, XR8a, alkyl (C1-6 ) -NR40R41, (C1-6) alkyl -COOR8b; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group F; wherein the aryl is naphthyl or substituted phenyl; In which heteroaryl a mono or bicyclic system containing 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; at

that heteroalicyclic is a 3 to 7 membered monocyclic ring that may contain 1 to 2 heteroatoms in the ring structure and that may be fused to a benzene or pyridine ring;

D is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56 , hydroxy, cyano and XR57;

X is selected from the group consisting of NH, NCH3 O and S;

E is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57, SO2-C1-6 alkyl and SO2Ph, wherein heteroaryl is a monocyclic system containing 3 to 7 ring atoms, including 1 to 4 heteroatoms;

F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen , nitro, -C (O) R57, benzyl, NR42C (O) -alkyl (C1-6), -NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) heteroalicyclic, 4, 5 or 6-membered ring cyclic N-lactam, -NR42S (O) 2-C 1-6 alkyl, -NR42S (O) 2 (C3-6) cycloalkyl, -NR42S (O) 2-aryl, -NR42S (O) -heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-C 1-6 alkyl, S (O) 2-aryl, -S (O) 2 NR42R43, NR42R43, (C1-6) -C (O) NR42R43, C (O) NR42R43, NHC (O) NR42R43, OC (O) NR42R43, NHC (O) OR54, (C1-6) -NR42R43 alkyl , COOR54 and (C1-6) alkyl -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which the aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O ) R57, benzyl, -NR48C (O) -alkyl (C1-6), NR48C (O) -cycloalkyl (C3-3), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O ) -heteroalicyclic, a 4, 5 or 6-membered ring cyclic N-lactam, -NR48S (O) 2-C 1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), -NR48S ( O) 2-aryl, -NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, (C1-6) alkyl C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54, alkyl (C1-6) -NR48R49 COOR54 and alkyl (C1-6) -COOR54; in which the aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R7 is selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with one to three same or different substituents selected from the group F; in which for R7, R8, R8a,

R8b

 aryl is phenyl; heteroaryl a mono or bicyclic system containing 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine;

R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five equal substituents

or different selected from group F;

R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens

or from one to five identical or different substituents selected from the group F;

R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

R40 and R41 are independently selected from the group consisting of

(to)

 hydrogen;

(b)

 (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; Y

(C)

 (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; Y

wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three halogens

5 same or different or one to two same or different substituents selected from group F; wherein for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; with the proviso that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or

10 (b);

R42

 and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, alkoxy

15 (C1-6), cycloalkyl (C3-7), aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group G; wherein for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; Heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and

20 morpholine;

R46 is selected from the group consisting of H, OR57, and NR55R56;

R47 is selected from the group consisting of H, amino, halogen, phenyl and (C1-6) alkyl;

R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl;

R54 is selected from the group consisting of hydrogen and (C1-6) alkyl;

R54 'is (C1-6) alkyl;

R55 is selected from the group consisting of hydrogen and (C1-6) alkyl;

R56 is independently selected from the group consisting of hydrogen and (C1-6) alkyl; Y

R57 is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl, wherein A is selected from the group consisting of C1-6 alkoxy, aryl and heteroaryl; wherein said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoimidazolyl, benzoimidazolyl, benzoimidazolyl; and said aryl or heteroaryl is optionally substituted with one

or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl ; Y

Each of R9, R10, R11, R12, R13, R14, R15 and R16 are independently H or (C1-6) alkyl which may be optionally substituted with 1 to 3 equal or different halogens;

which comprises subjecting a compound H as defined in Claim 1 of the structure

to a Grignard acylation reaction, in which the acid chloride 1

it is reacted with compound H to form compound L

and reacting compound L with a compound Da of the structure

5 in the presence of an organometallic base to form a compound IIA.

Preferably, the above Grignard acylation reaction is carried out in the presence of C2H5MgCl in an organic solvent, 2-CH3THF and an organic base,

wherein the Grignard acylation reaction is carried out at a temperature in the range of about -40 to about -50 ° C, in which compounds IIA, L and H, R2 is F and R3 is H and

In which the reaction of compound L and compound Da is carried out at a temperature in the range of about -5 to about 5 ° C.

In another aspect of the present invention, there is provided a process for preparing the compound L having the structure

15 which includes the step of submitting the compound H of the structure

to a Grignard acylation reaction, in which the acid chloride 1

it is reacted with compound H to form compound L,

5 in which the Grignard acylation reaction is carried out in the presence of C2H5MgCl, in an organic solvent, 2-CH3THF, organic base, such as pyridine, at a temperature in the range of about -50 to about 25 ° C, preferably of about -40 to about -50 ° C and wherein in compounds L and H, R2 is F, R3 is H and R18 is H or alkyl.

In addition, according to the present invention, there is provided a process for preparing compound IIA which has the structure

which includes the step of reacting compound L, which is prepared by the above procedures, of the structure

15 with a compound Da of the structure

wherein A is selected from the group consisting of C1-6 alkoxy, aryl and heteroaryl; wherein said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl; Y

each of R9, R10, R11, R12, R13, R14, R15 and R16 is independently H or (C1-6) alkyl which may be optionally substituted with 1 to 3 equal or different halogens;

in the presence of an organometallic base to form compound IIA,

wherein the reaction is carried out at a temperature in the range of about -20 to about 50 ° C and where in compounds IIA and L, R2 is F, R3 is H and R18 is H or alkyl.

The above reaction is carried out at a temperature preferably in the range of about -5 to about 5 ° C.

Also disclosed herein is the N-1 crystalline form of derivative II of 1,2,3-triazole, whose crystalline structure is established by crystallographic analysis (Tables 1 and 2) and the volume properties are characterized by ray diffraction Powdered X (PXRD, Figure 5), differential scanning calorimetry (DSC, Figure 6), thermogravimetric analysis (TGA, Figure 7), as will be described in detail later in this document. Other techniques, such as solid state nuclear magnetic resonance imaging (SSRMN), IR, Fourier transform infrared spectroscopy (FT-IR) and Raman.

A stabilized amorphous form of derivative II of 1,2,3-triazole is also disclosed herein.

The N-1 form and the stabilized amorphous form of the 1,2,3-triazole derivative II disclosed herein can be characterized using various techniques, the operation thereof is well known to those skilled in the art. The shapes can be characterized and distinguished using single crystal X-ray diffraction, which is based on single-crystal unit cell measurements of a shape at an adjusted analytical temperature. A detailed description of the unit cells is provided in Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New York (1968), Chapter 3, which is incorporated herein by reference. As an alternative, the only configuration of atoms in spatial relation in the crystalline network can be characterized according to the observed fractional atomic coordinates. Another means of characterizing the crystalline structure is by powder X-ray diffraction analysis in which the observed or experimental diffraction profile is compared with that of the pure powder material or with a simulated profile obtained from crystallographic X-ray determination simple.

Other means of characterizing the form, such as solid-state nuclear magnetic resonance (SSRMN), IR, FT-IR, Raman, differential scanning calorimetry, thermogravimetric analysis and sorption-moisture isotherms can be used. These parameters can also be used in combination to characterize the object form.

Also disclosed herein is a stabilized amorphous form of derivative II of 1,2,3-triazole which is prepared by flash evaporation of a solution of Form N-1 of derivative II of 1,2,3-triazole in a suitable solvent and can be characterized by a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 1.

Alternatively, the stabilized amorphous form disclosed above of derivative II of 1,2,3-triazole can be prepared by flash evaporation of a solution of Form N-1 of derivative II of 1,2,3-triazole in a suitable solvent and It can be characterized by a powder X-ray diffraction pattern (PXRD) observed substantially as shown in Figure 2.

In addition, the stabilized amorphous form disclosed above of derivative II of 1,2,3-triazole can be prepared by spray drying a solution of Form N-1 of derivative II of 1,2,3-triazole in a suitable solvent and It can be characterized by the powder X-ray diffraction pattern substantially as shown in Figure 3.

In addition, the stabilized amorphous form disclosed above of derivative II of 1,2,3-triazole can be prepared by spray drying a solution of Form N-1 of derivative II of 1,2,3-triazole in a suitable solvent and it can be characterized by the modulated differential scanning calorimetry thermogram (open vessel) substantially as shown in Figure 4a.

In addition, the stabilized amorphous form previously disclosed from derivative II of 1,2,3-triazole can be prepared by spray drying a solution of Form N-1 of derivative II of 1,2,3-triazole in a suitable solvent and can be characterized by the modulated differential scanning calorimetry thermogram (hermetically sealed container) substantially as shown in Figure 4b.

The N-1 crystalline form of derivative II of 1,2,3-triazole can be characterized by unit 10 cell parameters substantially the same as indicated below:

Cell dimensions:

a = 39,2481 (14) Å

b = 5.5577 (2) Å

c = 21.8072 (10) Å

15 a = 90 °

1 = 122,399 (4) °

Y = 90 °

C2 / c space group

in which the crystalline form is approximately 25 ° C

20 and single crystal crystallographic data are shown in Table 1.

Also described herein, the crystalline N-1 form of derivative II of 1,2,3-triazole can be characterized by fractional atomic coordinates substantially as listed in Table 2.

Also described herein, the crystalline Form N-1 of derivative II of 1,2,3-triazole can be characterized by simulated and substantially observed X-ray powder diffraction patterns as shown in Figure 5.

Also described herein, the crystalline Form N-1 of derivative II of 1,2,3-triazole can be characterized by a powder X-ray diffraction PXRD pattern having the following 20 values (CuKaI = 1.5418 Å) 5.3 ± 0.1, 8.1 ± 0.1, 9.6 ± 0.1, 16.2 ± 0.1, 17.0 ± 0.1, 19.6 ± 0.1, 20.7 ± 0.1 and 23.0 ± 0.1.

Also described herein, the crystalline Form N-1 of derivative II of 1,2,3-triazole can

30 characterized by a differential scanning calorimetry (DSC) thermogram (open vessel) substantially as shown in Figure 6, having an initial endotherm at approximately 279 ° C.

Also described herein, the crystalline Form N-1 of derivative II of 1,2,3-triazole can be characterized by a thermogravimetric analysis (TGA) curve (open container) having a negligible weight loss up to about 100 ° C, substantially as shown in Figure 7.

Also described herein, the crystalline Form N-1 of derivative II of 1,2,3-triazole can be characterized by the moisture-sorption isotherm, substantially as shown in Figure 8 which shows approximately 0.1 % weight gain in the range of about 25 to about 75% RH @ 25 ° C.

The various crystalline forms of derivative I of 1,2,4-triazole are disclosed in provisional US patent application No. 40. 60 / 626,148 filed on November 9, 2004.

SUMMARY DESCRIPTION OF THE FIGURES

Figure 1 shows a differential scanning calorimetry (DSC) thermogram of the stabilized amorphous form of 1,2,3-triazole derivative II prepared by flash evaporation;

Figure 2 shows a powder X-ray diffraction pattern (PXRD) observed in the stabilized amorphous form 45 of the 1,2,3-triazole derivative prepared by flash evaporation;

Figure 3 shows an observed powder X-ray diffraction pattern (experimental at 24 ± 3 ° C) of the stabilized amorphous form of 1,2,3-triazole derivative II prepared by spray drying by;

Figure 4a shows a differential scanning calorimetry (DSC) thermogram of sterile amorphous 1,2,3-triazole derivative II (open vessel) prepared by spray drying;

Figure 4b shows a differential calorimetry thermogram (DSC) of the stabilized amorphous 1,2,3-triazole derivative II (hermetically sealed container) prepared by spray drying;

Figure 5 shows calculated (simulated) X-ray powder diffraction patterns (25 ° C) and observed representative (experimental at room temperature) (CuKaI = 1.5418 A) of crystals of crystalline Form N-1 of derivative II of 1,2,3-triazole;

Figure 6 shows a differential scanning calorimetry (DSC) thermogram representative of Form N-1 crystals of derivative II of 1,2,3-triazole;

Figure 7 shows a thermogravimetric analysis (TGA) curve representative of the crystals of Form N-1 of derivative II of 1,2,3-triazole; Y

Figure 8 shows a representative moisture-sorption isothermal crystals of Form N-1 of derivative II of 1,2,3-triazole.

Detailed description of the invention

Since the compounds obtained from the processes of the present invention may have asymmetric centers and, therefore, appear in the form of mixtures of diastereomers and enantiomers, the methods of the present invention include the individual diastereomeric and enantiomeric forms of the compounds in addition to the mixtures thereof.

Definitions

The term " C1-6 alkyl " as used herein and in the claims (unless otherwise specified) refers to straight or branched chain alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl , hexyl and the like.

" Halogen " It refers to chlorine, bromine, iodine or fluorine.

A group " arilo " refers to fully fused monocyclic or polycyclic carbon groups (i.e. rings that share adjacent pairs of carbon atoms) that have a fully conjugated pi electron system. They are non-limiting examples of aryl phenyl, naphthalenyl and anthracenyl groups. The aryl group may be substituted or unsubstituted. When substituted, the aryl group or groups are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NRxRy, in which Rx and Ry are independently selected Among the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, C-carboxy, sulfonyl, trihalomethyl and combined, a five or six membered heteroalicyclic ring.

As used herein, a group "heteroaryl" refers to a monocyclic or condensed ring group (i.e., rings that share an adjacent pair of atoms) having in the ring or rings one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, which has a fully conjugated pi electron system. Unless otherwise indicated, the heteroaryl group may be attached to both a carbon and nitrogen atom in the heteroaryl group. It should be appreciated that the term "heteroaryl" is intended to include a parental heteroaryl N-oxide if said N-oxide is chemically possible as is known in the art. Non-limiting examples are of heteroaryl furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahyiopropyranyl, pyrazolyl, quinzolyl, pyrazyl, quinolinyl , purinyl, carbazolyl, benzoxazolyl, benzoimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine, triazinyltriazole, tetrazinyl and tetrazolyl. When substituted, the substituted group or groups are preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro carbonyl, O-carbamyl, N-carbamyl, C-amido, Namido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, amino and -NRxRy, in which Rx and Ry are as defined previously.

As used herein, a group "heteroalicyclic" refers to a monocyclic or condensed ring group having one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur in the ring or rings. The rings can also have one or more double bonds. However, the rings do not have a fully conjugated pi electron system. Non-limiting examples are heteroalicyclic, azetidinyl, piperidyl, piperazinyl, imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl, thiomorpholinyl and tetrahydropyranyl groups. When substituted, the substituted group or groups is preferably one or more selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy,

heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-amido, N-amido, C-amido, N C-carboxy, Ocarboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl, amino and -NRxRy, in which Rx and Ry are as defined above.

A group " alkyl " refers to a saturated aliphatic hydrocarbon that includes linear and modified chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms (provided that a numerical range; for example, "1-20", is indicated herein, means that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium-sized alkyl having from 1 to 10 carbon atoms. More preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the group or groups of substituents is one or more individually selected trihaloalkyl entity, cycloalkyl, aryl, heteroaryl, heteroarilcíclico, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo , nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, C-thioamido, Namido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanes and combined, a five or six membered heteroalicyclic ring.

A group "cycloalkyl" refers to a monocyclic ring group or completely carbon condensate (i.e. rings that share a pair of adjacent carbon atoms), in which one or more rings do not have a fully conjugated pi electron system. Non-limiting examples are cycloalkyl, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene and adamantane groups. A cycloalkyl group may be substituted or unsubstituted. When substituted, the group or groups of substituents are preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroarylcyclic, hydroxy, alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halo nitro, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, Nthiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido, trihalomethanes silyl, guanyl, guanidino, ureido, phosphonyl, amino and NRxR and Rx and Ry being as defined above.

A group "alkenyl" refers to an alkyl group, as defined herein, which consists of at least two carbon atoms and at least one carbon-carbon double bond.

A group "alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond.

A group "hydroxy" refers to a group -OH.

A group " alkoxy " it refers to both an -O-alkyl group and an -O-cycloalkyl group as defined herein.

A group " ariloxi " it refers to both an -O-aryl group and an -O-heteroaryl group, as defined herein.

A group "heteroaryloxy" refers to a heteroaryl-O- group, being heteroaryl as defined herein.

A group "heteroalicycloxy" refers to a heteroalicyclic-O- group, being heteroalicyclic as defined herein.

A group "thiohydroxy" refers to a group -SH.

A group "thioalkoxy" it refers to both an S-alkyl group and a -S-cycloalkyl, as defined herein.

A group "thioaryloxy" it refers to both an -S-aryl group and an -S-heteroaryl group, as defined herein.

A group "thioheteroaryloxy" refers to a heteroaryl-S- group, being with heteroaryl as defined herein.

A group "thioheteroalicycloxy" refers to a heteroalicyclic group-S-, being heteroalicyclic as defined herein.

A group "carbonyl" refers to a group -C (= O) -R ", in which R " is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl (attached by a ring carbon) and heteroalicyclic (linked by a ring carbon), each being as defined herein. document.

A group "aldehyde" refers to a carbonyl group, in which R " It is hydrogen. A group "thiocarbonyl" refers to a group -C (= S) -R ", R " as defined in this document. A group " Keto " refers to a group -CC (= O) C-, in which carbon at one or both ends of C = O can

be alkyl, cycloalkyl, aryl or a carbon of a heteroaryl or heteroalicyclic group. A group "trihalomethanecarbonyl" refers to a group Z3CC (= O) -, where Z is halogen. A group "C-carboxy" refers to groups -C (= O) O-R ", R " as defined in this document. A group "O-carboxy" refers to a group R " C (-O) O-, where R " as defined in this document. A group "carboxylic acid" refers to a C-carboxy group, in which R " It is hydrogen. A group "trihalomethyl" refers to a group -CZ3, in which Z is a halogen group as defined in the

present document A group "trihalomethanesulfonyl" refers to groups Z3CS (= O) 2-, where Z is as defined above. A group "trihalomethanesulfonamido" refers to a group Z3CS (= O) 2NRx-, where Z and Rx are as defined in the

present document

A group "sulfinyl" refers to refers to a group -S (= O) -R ", being R " as defined herein document and also as a single link; that is, -S (O) -. A group "sulfonyl" refers to a group -S (= O) 2R ", R " as defined in this document and,

also as a single link; that is, -S (O) 2-.

A group "S-sulfonamido" refers to a -S (= O) 2NRXRY, where Rx and Ry are as defined herein. A group "N-sulfonamido" refers to a group R &S; = 0) 2NRX-, where Rx is as defined herein

document. A group "O-carbamilo" refers to a -OC (= O) NRxRy as defined herein. A group "N-carbamilo" refers to a group RxOC (= O) NRy, where Rx and Ry are as defined herein.

document.

A group " O-tiocarbamilo " refers to a group -OC (= S) NRxRy, where Rx and Ry are as defined herein. A group " N-tiocarbamilo " refers to a group RxOC (= S) NRy-, where Rx and Ry are as defined herein.

document. A group "amino" refers to a group -NH2. A group "C-amido" refers to a group -C (= O) NRxRy, where Rx and Ry are as defined herein.

document.

A group "C-thioamido" refers to a group -C (= S) NRxRy, where Rx and Ry are as defined herein. A group "N-amido" refers to a group RxC (= O) NRy-, where Rx and Ry are as defined herein.

document.

A 4, 5 or 6-membered cyclic ring N-lactam refers to rings of 4, 5 or 6 atoms that contain a single amide group as two of the atoms in the ring are attached to the parent moiety in the amide nitrogen . A group "ureido" refers to a group NRxC (= O) NRyRy2, where Rx and Ry are as defined herein.

document and Ry2 is defined in the same way as Rx and Ry.

A group " guanidino " refers to a group -RxNC (= N) NRyRy2, being * Rx, Ry and Ry2 as defined herein. A group " guanilo " refers to a group RxRyNC (= N) -, where Rx and Ry are as defined herein.

document. A group "cyano" refers to a group -CN.

A group "sililo" refers to a -Yes (R ") 3, where R " as defined in this document.

A group "phosphonyl" refers to a P (= O) (ORx) 2, where Rx is as defined herein.

A group "hydrazino" refers to a group -NRxNRyRy2, where Rx, Ry and Ry2 are as defined herein.

Any two adjacent R groups can be combined to form an additional aryl, cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initially bearing those R groups.

It is known in the art that nitrogen atoms in heteroaryl systems can be " participants in a double bond of the heteroaryl ring " and this refers to the form of double bonds in the two tautomeric structures comprising five-membered ring heteroaryl groups. This determines whether the nitrogen can be substituted as the chemists will well understand in the art. The disclosure and claims of the present invention are based on general known principles of chemical bonding. It is understood that the claims do not encompass structures that are known to be unstable or cannot exist, based on the literature.

Physiologically acceptable salts and prodrugs of the compounds described herein are within the scope of the present invention. The term "pharmaceutically acceptable salt", as used herein and in the claims, is intended to include non-toxic base addition salts. Suitable salts include those obtained from organic or inorganic acids, such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, acotinic acid, salicylic acid, phthalic acid and the like. The term "pharmaceutically acceptable salt", as used herein, is also intended to include salts of acidic groups, such as a carboxylate, with counterions, such as ammonium, alkali metal salts, particularly sodium or potassium, metal salts alkaline earth metals, particularly calcium or magnesium and salts with suitable organic bases, such as lower alkylamines (methylamine, ethylamine, cyclohexylamine and the like) or with substituted lower alkylamines (for example, hydroxy substituted alkylamines, such as diethanolamine, triethanolamine or tris (hydroxymethyl) -aminomethane) or with bases, such as piperidine or morpholine.

Abbreviations

The following abbreviations, being most of the same conventional abbreviations well known to those skilled in the art, are used throughout the description of the invention and the examples. Some of the abbreviations used are as follows:

h = hour or hours

ta = room temperature

mol = mol or moles

mmol = millimol or millimoles

g = gram or grams

mg = milligram or milligrams

ml = milliliter or milliliters

TFA = Trifluoroacetic Acid

DCE = 1,2-Dichloroethane

CH2Cl2 = Dichloromethane

TPAP = Tetrapropylammonium Perrutenate

THF = Tetrahydrofuran

DEPBT = 3- (Diethoxyphosphoryloxy) -1,2,3-benzotriazin-4 (3H) -one

DMAP = 4-Dimethylaminopyridine

P-EDC = 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide supported by polymer

EDC = 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide.

DMF = N, N-Dimethylformamide

Hunig Base = N, N-Diisopropylethylamine DMA = Dimethylacetamide AcOH = Acetic acid IPA = Isopropyl alcohol PVP = Polyvinylpyrrolidone (Plasdone, Povidone) SDI = Spray-dried intermediate PEG = Polyethylene glycol mCPBA = Meta-chloroperol-pyrolidine-Azo-pyrolidine-Pyrol-azo-pyrol-1 4-azaindole = 1H-Pyrrolo [3,2-b] pyridine 5-azaindole = 1H-Pyrrolo [3,2-c] pyridine 6-azaindole = 1H-Pyrrolo [2,3-c] pyridine 7-azaindole = 1H -Pyrrolo [2,3-b] pyridine PMB = 4-Methoxybenzyl DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone OTf = Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh = 1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC = 1- (3-Dimethylaxninopropyl) -3-ethylcarbodiimide TMS = Trimethylsilyl DCM = Dichloromethane DCE = Dichloroethane MeOH = Methanol THF = Tetrahydrofuran EtOAc = Ethyl Acetate LDA = Diisopropyl Li = Diisopropyl Li = Diisopropyl Li = Diisopropyl Li = Diisopropyl Li 6-tetramethylpiperidinyl·lithium DME = Dimethoxyethane DIBALH = Diisobutylaluminum hydride HOBT = 1-Hydroxybenzotriazole CBZ = Benzyloxic arbonyl PCC = Pyridinium Chlorochromate Me = Methyl Ph = Phenyl

Crystalline forms

Also described herein is the crystalline form N-1 and the stabilized morphine form of derivative II of 1,2,3-triazole.

As used herein "polymorph" It refers to forms that have the same chemical composition but different spatial configurations of molecules, atoms and / or ionic forms of the crystal.

As used herein " solvato " it refers to a crystalline form of the molecule and / or ions that also contain molecules of a solvent or solvents incorporated in the crystalline structure. Solvent molecules in the solvate may be present in a regular configuration and / or unordered configuration. The solvate may contain a stoichiometric or non-stoichiometric amount of solvent molecules. For example, a solvate with a non-stoichiometric amount of solvent molecules can result in partial loss of the solvate solvent.

Samples of the crystalline forms can be provided with substantially pure phase homogeneity, indicating the presence of a dominant amount of a single crystalline form and, optionally, smaller amounts of one or more different crystalline forms. The presence of more than one crystalline form in a sample can be determined by techniques, such as X-ray powder diffraction (PXRD) or solid-state nuclear magnetic resonance spectroscopy (SSRMN). For example, the presence of extra peaks in the comparison of an experimentally measured PXRD pattern with a simulated PXRD pattern may indicate more than one crystalline form in the sample. Simulated PXRD can be calculated from single crystal X-ray data (see Powder Diffraction Simulation and Srtucture Display, Materials Data Inc., Livermore, California, United States, 2001). Preferably, the crystalline form has a substantially pure phase homogeneity as indicated by less than 10%, preferably less than 5% and more preferably less than 2% of the total peak area in the experimentally measured PXRD pattern that comes from extra peaks. that are absent from the simulated PXRD pattern. Most preferred is a crystalline form that has a substantially pure phase homogeneity with less than 1% of the total peak area in the experimentally measured PXRD pattern that comes from extra peaks that are absent from the simulated PXRD pattern.

Procedures for the preparation of crystalline forms are known in the art. The crystalline forms can be prepared by a variety of procedures, including, for example, crystallization or recrystallization in a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization in a supercritical lump and jet spray. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture include, for example, evaporation of the solvent, decrease of the temperature of the solvent mixture, sowing with crystals a supersaturated solvent mixture of the molecule and / or salt. , lyophilizing the solvent mixture and adding anti-solvents (counter-solvents) to the solvent mixture. High performance crystallization techniques can be employed to prepare crystalline forms, including polymorphs.

Drug crystals, including polymorphs, methods of preparation and characterization of drug crystals are described in Solid-State Chemistry of Drugs, S.R. Byrn, R.R. Pfeiffer and J.G. Stowell, 2nd Edition, SSCI, West Lafayette, Indiana (1999).

For crystallization techniques employing solvent, the choice of solvent or solvents normally depends on one or more factors, such as compound solubility, solvent vapor pressure crystallization technique. Solvent combinations may be employed, for example, the compound can be solubilized in a first solvent to provide a solution, followed by the addition of an anti-solvent to decrease the solubility of the compound in the solution and to provide crystal formation. An anti-solvent is a solvent in which the compound has low solubility. Suitable solvents for preparing crystals include polar and non-polar solvents.

In a process for preparing crystals, derivative II of 1,2,3-triazole or a salt thereof is suspended and / or stirred in a suitable solvent to provide a suspension, which can be heated to stimulate dissolution. The term "suspension", as used herein, refers to a saturated solution of Compound II or a salt thereof, which may also contain an additional amount of Compound II or a salt thereof to provide a heterogeneous mixture. of Compound II or a salt thereof and a solvent at a given temperature. Suitable solvents in this regard include, for example, polar aprotic solvents, polar protic solvents and mixtures of two or more of these as described herein.

Sowing crystals can be added to any crystallization mixture to stimulate crystallization. As will be apparent to the person skilled in the art, sowing is used as a means of controlling the growth of a particular crystalline form or as a means of controlling the particle size distribution of the crystalline product. Therefore, the calculation of the quantity of seeds needed depends on the size of the available seed and the desired size of an average product particle as described, for example, in "Programmed cooling of batch crystallizers," J.W. Mullin and J. N'yvlt, Chemical Engineering Science (1971) 26: 369-377. In general, small seeds are needed to effectively control the growth of crystals in the batch. They can

Generate small seeds by screening, grinding or micronizing larger crystals, or by microcrystallization of solutions. Care must be taken that the grinding or micronization of crystals does not result in any change in the crystallinity of the desired crystalline form (i.e., change to amorphous or other polymorph).

A cooled mixture can be filtered under vacuum and the washed solids can be washed with a suitable solvent, such as cold crystallization solvent and dried in a nitrogen purge to provide the desired crystalline form. Isolated solids can be analyzed by a suitable spectroscopy or analytical technique, such as SSRMN, IR, FT-IR, Raman, DSC, PXRD or the like, to ensure the formation of the preferred crystalline form of the product. The resulting crystalline form is normally produced in an amount of more than 70% by weight of isolated yield, but preferably more than 90% by weight based on the weight of 1,2,3-triazole derivative II originally employed in the process of crystallization. The product can be comlected or passed through a mesh screen to undo the product groups, if necessary.

Crystalline forms can be prepared directly from the reaction medium of the final process step to prepare derivative II of 1,2,3-triazole. This can be achieved, for example, by using in the final process step a solvent or solvent mixture from which derivative II of 1,2,3-triazole can be crystallized. Alternatively, crystalline forms can be obtained by evaporation, by distillation or solvent addition techniques. Suitable solvents for this purpose include any of the solvents described herein, including polar prototypes, such as alcohols and polar aprotic solvents, such as ketones.

As a general guide, the reaction mixture can be filtered to remove any unwanted impurity, inorganic salts and the like, followed by washing with reaction solvent or crystallization. The resulting solution can be concentrated to remove excess solvent or gaseous constituents. If distillation is used, the final amount of distillate collected may vary, depending on process factors including, for example, vessel size, stirring capacity and the like. As a general guide, the reaction solution can be distilled at approximately {fraction (1/10)} of the original volume before replacing the solvent. Samples of the reaction can be taken and tested to determine the extent of the reaction and the weight% of product according to conventional processing techniques. If desired, more reaction solvent may be added or removed to optimize the concentration of the reaction. Preferably, the final concentration is adjusted to about 50% by weight, at which point a suspension normally results.

It may be preferred to add solvents directly to the reaction vessel without distilling the reaction mixture. Preferred solvents for this purpose are those that can ultimately participate in the crystalline lattice as described above regarding solvent exchange. Although the total concentration may vary depending on the desired purity, recovery and the like, the final concentration of 1,2,3-triazole derivative II in the solution is preferably from about 4% to about 7%. The reaction mixture can be stirred followed by solvent addition and simultaneous heating. By way of illustration, the reaction mixture can be stirred for about 1 hour while heating at about 70 ° C. The reaction is preferably filtered hot and washed with the reaction solvent, the added solvent or a combination thereof. Sowing crystals can be added to any crystallization solution to initiate crystallization.

The various forms described herein can be distinguished from each other through the use of various analytical techniques known to a person skilled in the art. Such techniques include, but are not limited to, solid-state nuclear magnetic resonance spectroscopy (SSRMN), IR, FT-IR, Raman, X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC) and / or thermogravimetric analysis (TGA).

One skilled in the art will appreciate that an X-ray diffraction pattern can be obtained with a measurement error that depends on the measurement conditions employed. In particular, it is generally known that the intensities of an X-ray diffraction pattern may fluctuate depending on the measurement conditions employed, the shape or morphology and the orientation of the crystal. In addition, it should be understood that the relative intensities may also vary depending on the experimental conditions and, therefore, the exact order of intensity should not be taken into account. In addition, a diffraction angle measurement error for a conventional X-ray diffraction pattern is usually about 0.2% or less, preferably about 0.1% (as described hereinbelow) and said Degree of measurement error should be taken into account as belonging to the diffraction angles mentioned above.

New procedures

The process of the invention for preparing the 1,2,3-triazole derivative IIA is shown in detail in the Scheme

II.

The sequence of reactions in Scheme II shows a general organization of the stages of the starting material b to the final stage which results in derivative IIA of 1,2,3-triazole (or II) (Scheme II). As shown below, each of the steps may include a variety of reaction conditions for

Get the desired product. This is further shown in the functional examples set forth hereinbelow.

With respect to Scheme II, a synthesis of indole Leimgruber-Batcho is indicated in Stages 1, 2 and 3. Therefore, in Step 1, compound b. an enamine formation is subjected, in which compound b is mixed with an organic solvent, such as N, N-dimethyl formamide (DMF) and DMF-dimethyl acetal c.

using a molar ratio of acetal c: compound b in the range of about 3.5: 1 1 to about 5: 1, preferably from about 3.75: 1 to about 4: 1 The reaction mixture

10 is heated to a temperature in the range of about 110 to about 130 ° C and volatiles are removed by distillation to form compound F. The reaction mixture is cooled to a temperature in the range of about 5 to about 15 ° C, add water and after stirring, compound F. is recovered.

In Step 2, compound F is cycled through a reduction reaction to form compound Fa. The

The reduction is made in the presence of platinum on carbon (available as catalyst CP126, Escat 261 or Escat 160 - Englehard Industries), although a variety of catalysts can be useful in such reduction, including palladium on carbon (Pd / C), Pd- C, Zn, Fe or sodium dithionate. The reduction is performed at a pressure of hydrogen (H2) in a range of about 0.1 MPa (15 psi) to about 0.41 MPa (60 psi) at a temperature in the range of about 15 to about 35 ° C.

The compound Fa is formed by treating it with an acid, such as hydrochloric acid to hydrolyze the compound Fa and form an amine compound G · HCl salt (Step 3).

In Step 4, the amine compound G · HCl salt is converted into derivative H of 1,2,3-triazole by treating compound G · HCl salt with a base, such as K3PO4, methylsulfonyl hydrazide, an organic solvent, such as acetonitrile and 2,2-dimethoxy-acetaldehyde in water. The preparation of the amine compound G · HCl salt to give derivative H of 1,2,3triazole is carried out using a molar ratio of K3PO4 with respect to the compound G · HCl salt in the range of about 0.5: 1 1 a about 2: 1, preferably about 1.0: 1 to about 1.1: 1, a molar ratio of methylsulfonyl hydrazide: compound G · HCl salt in the range of 1.0: 1 to about 2.5: 1, preferably from about 1.4: 1 to about 1.7: 1 and a molar ratio of 2,2-dimethoxyacetaldehyde: compound G · HCl salt in the range of about 1.0: 1 to about 2.2: 1, preferably from about 1.2: 1 to about 1.4: 1, at a temperature

10 in the range of about 30 to about 130 ° C, preferably about 50 to about 80 ° C.

As seen in Scheme II, derivative H of 1,2,3-triazole can also be prepared starting from compound d. A synthesis of indole Leimgruber-Batcho is indicated in Stages 1A and 2A. In Step 1A, compound d is converted by enamine formation in compound J, wherein compound d is treated with

An organic base, such as lithium methoxide (using a molar ratio of base: compound d in the range of about 0.05: 1 to about 0.15: 1), an organic solvent, such as N, N-dimethylformamide (DMF) and DMF-dimethyl acetal c.

using a molar ratio of acetal c: compound d in the range of about 3: 1 a

20 approximately 8: 1. The reaction mixture is heated at a temperature in the range of about 80 to about 85 ° C. Compound J is formed in this way.

In Step 2A, compound J is cycled through a reduction reaction employing any of the catalysts and reaction conditions set forth above with respect to Step 2 in Scheme II, in which compound F is cycled to give compound F'. However, the reduction of compound J to give the

Compound K is performed at a temperature in the range of about 25 to about 50 ° C.

In Step 3, a compound K is caused to undergo a coupling reaction, in which compound K is treated with a base, such as K2HPO4, a copper catalyst, such as Cu2O and 1,2,3-triazole Y '.

When R18 is H or alkyl and the reaction is heated to a temperature in the range of about 120 to

At about 160 ° C to form derivative H of 1,2,3-triazole H, the coupling reaction is performed using a molar ratio of base: compound K in the range of about 0.8: 1 to about 1.2: 1, preferably from about 0.9: 1 to about 1.1: 1, a molar ratio of Cu2O: compound K in the range of about 0.1: 1 to about 1.0: 1, preferably about 0.15 : 1 to about 0.25: 1 and a molar ratio of 1,2,3-triazole e: compound K in the

35 ranges from about 10: 1 to about 30: 1, preferably from about 13: 1 to about 18: 1.

Compound H can also be prepared by reacting compound Ga

with the compound G neutralized and K2HPO4 (potassium phosphate, dibasic) in the presence of organic solvents such as

Dimethylacetamide / acetonitrile / ethyl acetate. For carrying out the above reaction, compound Ga will be used in a molar ratio with respect to compound G in the range of about 1.5: 1 to about 1.2: 1, preferably about 1.2: 1 to about 1.3: 1 and the K2HPO4 is

it will employ in a molar ratio with respect to compound G in the range of about 1.4: 1 to about 1: 1, preferably from about 1.2: 1 to about 1.3: 1.

In Step 5, compound H is subjected to Grignard acylation, in which compound H is mixed with an organic solvent, such as 2-methyltetrahydrofuran (2-MeTHF) or a mixture of toluene: methylene chloride (1 : 2 to 5 2: 1, preferably 2: 1), the resulting suspension is cooled to a temperature in the range of about -5 to about -15 ° C and the cooled suspension is treated with a solution of a Grignard reagent, such as C2H5MgCl in THF (Grignard: THF molar ratio of about 2: 1 to about 2.5: 1, preferably 2.2: 1) (C2H5MgCl molar ratio: compound H in the range of about 3.4: 1 to about 4: 1, preferably from about 3.5: 1 to about 3.6: 1) while remaining in the range of about -15 ° C to about 0 ° C. An organic base, such as pyridine, picoline or lutidine, is added to the reaction mixture in a molar ratio with respect to substrate H in the range of about 0.5: 1 to about 1.5: 1. The reaction is cooled to a temperature of about -40 ° C to about -50 ° C and methyl chloroxoxoacetate (molar ratio of acid chloride: substrate H in the range of about 3.4: 1 to about 5: 1, preferably from

15 about 3.5: 1 to about 4: 1) while maintaining an internal temperature in the range of about -50 ° C to about -40 ° C. The reaction is heated to a temperature in the range of about -15 to about -5 ° C and compound L. is recovered.

Then, in Step 5, compound L is coupled with the piperazine derivative Da

20 using a molar ratio of Da: L in the range of about 1.3: 1 to about 1.1: 1, preferably from about 1.22: 1 1 to about 1.1: 1, an organic base, such as sodium t-butoxide, potassium t-butoxide or lithium t-butoxide (base molar ratio with respect to L in the range of about 2.5: 1 1 to about 3.1: 1) is added and the reaction is stirred at a temperature in the range of about 15 to about 22 ° C and then cooled to about -5 ° C to

25 approximately 5 ° C. Compound II is formed and can be recrystallized as described hereinbelow and in the Examples.

The starting materials, b and d in Scheme II, are known in the art.

The 1,2,3-triazole derivative IIA produced as described above (wherein R18 is H, R2 is F, R3 is H, R9 to R16 is H and A is phenyl, compound II) is in the form of Form N-1 crystals that are characterized as

30 described above.

The crystalline Form N-1 of derivative II of 1,2,3-triazole is obtained by recrystallizing or suspending derivative II of 1,2,3-triazole (such as, form P-2 or form P-6 of derivative 1,2,3-Triazole II) in a suitable solvent, preferably a mixture of ethanol and water in a v / v ratio of ethanol: water in the range of about 6: 1 1 to about 1: 1, preferably of about 4: 1 to about 2: 1.

Recrystallization or resuspension in other solvents, such as (1) aqueous acetonitrile, (2) acetonitrile, methanol and dichloromethane (such as in which the starting material is the P-6 form), (3) isopropyl alcohol (such as in which the starting material is in the form P-2) or (4) solvent mixtures containing dichloromethane, methanol, ethanol, isopropyl alcohol and / or acetonitrile, can also be used to produce the material of the crystalline Form N -one.

The crystalline form N-1 of derivative II of 1,2,3-triazole can also be obtained by heating the P-2 form of derivative II of 1,2,3-triazole at a temperature of about 265 ° C (at about 10 ° C / min) and cooling to room temperature.

The P-2 form of derivative II of 1,2,3-triazole can be prepared by crystallization of derivative II of 1,2,3-crude with methanol or crystallization of derivative II of 1,2,3-triazole with crude methanol followed by gel chromatography

45 silica using hexane / ethyl acetate / trichloromethane and methanol.

The P-6 form of derivative II of 1,2,3-triazole can be prepared by crystallization of derivative II of crude 1,2,3-triazole with methanol, followed by chromatography on silica gel, using hexane / acetate. ethyl / dichloromethane / methanol.

The N-1 crystalline form of derivative II of 1,2,3-triazole can be converted into a preferred stabilized amorphous form that can be prepared in accordance with the present invention by flash evaporation, spray drying or any other techniques thereof.

The stabilized amorphous form of derivative II of 1,2,3-triazole is prepared by solubilizing or suspending a mixture of

5 Form N-1 and a stabilizer in a suitable solvent system, heating the resulting mixture to a temperature to perform solubilization and subjecting the resulting solution to flash evaporation to form the stabilized amorphous form of derivative II of 1.2, 3-triazole

The stabilized amorphous form resulting from derivative II of 1,2,3-triazole will have improved solubility over the Starting Form N1 and will have improved oral bioavailability. The stabilizer used in the formation of the stabilized amorphous form 10 of derivative II of 1,2,3-triazole will work to inhibit the conversion of the return amorphous form to give the crystalline form N-1. Examples of stabilizers suitable for use herein include, but are not limited to, polyvinylpyrrolidone (PVP), PVP-vinyl acetate copolymer or PVP-vinyl acetate copolymer and d-a-tocopheryl polyethylene glycol 1000 (TPGS) succinate. However, derivative II of 1,2,3-triazole can be stabilized by other excipients, such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC)

15 or any other pharmaceutically acceptable excipient.

The following Examples are illustrative of the present invention.

Examples

Example 1

Preparation of Compound J 'from Compound da

The compound gives (800 g, 3.404 mol), lithium methoxide (12.9 g, 0.34 mol) and DMF (5.6 l) were loaded into a reactor

inert Korzun of 20 l. Then, DMF-dimethyl acetal c. (2.02 kg, 17.1 mol). The homogeneous solution

The resultant was heated to 80-85 ° C and maintained at that temperature until the HPLC analysis of the mixture of

Rough reaction indicated that there was less than 0.5% relative area of (RAP) of compound da. The reaction mixture was cooled to 5-10 ° C. Water (9 l) was loaded into the reactor, keeping the temperature below

45 ° C. The resulting suspension was cooled to 0-5 ° C and maintained at this temperature for 1 h. The crystals are

collected by filtration. The cake was washed with deionized water (6 L) and dried at 45 ° C under vacuum to give J 'as

of a light brown solid (890 g, 90%, HPLC AP 98.1). 1H NMR (300 MHz, d6-DMSO) 8 8.02 (d, JF-H = 4.2

Hz, 1H), 7.47 (dd, J = 13.0 Hz, JF-H = 1.7 Hz, 1H), 4.20 (d, J = 13.0 Hz, 1H), 3.14 ( s, 6H); 13C NMR (75 MHz, d630 DMSO): 8 153.9 (d, JF-C = 255 Hz), 151.6, 151.4, 141.9, 136.4 (d, JF-C = 27 Hz) , 131.0 (d, JF-C = 15 Hz), 126.1 (d, JF-C

= 2 Hz), 78.8.

Example 2

Preparation of Br, F-Azaindole, Compound K 'from Compound J' (Example 1)

Compound J '(450 g, 1,557 mol), catalyst Escat 261 (Pt / C) (90.0 g, 20% by weight in water) and THF (3.6 l) were loaded into a hydrogenation reactor of 5 inertized liters. The resulting suspension was allowed to stir at room temperature for 1 h. Hydrogen was added at a final pressure of 0.21 MPa (30 psi). The reactor was carefully heated to 45 ° C and maintained at this temperature until it was determined that the reaction was completed by an HPLC analysis process. The catalyst was filtered off and the cake was washed with THF (0.36 L). The solution was concentrated to a minimum volume of stirring by distillation under reduced pressure. Acetone was charged to the reactor to bring the total volume to 5.4 l. The acetone solution was heated just to reflux and water (3.5 L) was added keeping the temperature between 50-55 ° C. The resulting suspension was cooled to 05 ° C for a period of 1 h and maintained at this temperature for 1 h. The crystals were collected

10 by filtration, washed with deionized water and dehydrated for 1 h. The cake was dried at 40 ° C under vacuum to give K 'as an off-white solid (580 g, 87% yield, HPLC AP 99.5). 1H NMR (300 MHz, d6-DMSO) 8 7.94 (d, JF-H = 1.9 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 6.78, ( d, J = 3.0 Hz, 1H); 13C NMR (75 MHz, d6-DMSO) 8153.3 (d, JF-C = 252 Hz), 133.7 (d, JF-C = 9 Hz), 131.1, 123.6 (d, JF- C = 25 Hz), 122.8 (d, JF-C = 21 Hz), 119.0, 98.6; MS EN + 216.9 (M + 1).

15 Example 3

Preparation of Compound H 'from Compound K' (Example 2)

Compound K '(650 g, 3.02 mol) was loaded into a 12-liter inert reactor and followed by sequential addition of K2HPO4 (527 g, 3.02 mol), Cu2O (59 g, 0.60 mol ) and 1,2,3-triazole (3133 g, 45.3 mol). The mixture was stirred and heated at 145 ° C under a nitrogen atmosphere for 24 h. The batch was cooled to 60 ° C and THF (6.5 L) was loaded. The bath was filtered and the filter cake was washed with THF (5.2 L). The combined THF streams were concentrated to a minimum agitation volume. The batch was cooled to <30 ° C and 2N HCl (13 L) was added. The batch was aged at 20 ~ 25 ° C for 20 min. with stirring and then filtered. The filter cake was washed with 2N HCl (5.2 L) DI deionized water. The wet cake was washed with 95% EtOH (2.6 L) and dried to produce H 'as a yellow solid

25 clear (552 g, 45% yield). pf. 205 ~ 206 ° C; 1H NMR (300 MHz, d6-DMSO) 8 12.12 (s, 1H), 8.91 (s, 1H), 8.03 (s, 1H), 8.01 (d, JF-H = 1, 7 Hz, 1H), 7.68 (d, J = 3.2 Hz, 1H), 6.75 (d, J = 3.2 Hz, 1H), 3.30 (s, 1H); 13C NMR (75 MHz, d6-DMSO) 8 152.5 (d, JF-C = 252 Hz), 133.8, 132.3, 130.7, 125.2 (d, JF-C = 22 Hz) , 124.4 (d, JF-C = 10 Hz), 122.3, 121.1 (d, JF-C = 26 Hz), 98.0; HMS calc. for C9H7FN5 204.0685, found 204.0684; Anal Calc. for C9H7FN5: C, 53.20; H, 2.97; N, 34.47. Found: C, 52.99; H, 2.88; N, 34.55.

Example 4 Preparation of Compound F 'from Compound ba

2-amino-5-fluoro-3-nitro-4-picoline (Compound ba) (50.0) was loaded in a 2-liter vessel equipped with a top stirrer, a Dean-Stark trap and a temperature probe. g, 292 mmol). DMF5 DMA (Compound c) (158.5 ml, 1.17 mol, 4 equiv.) Was added followed by DMF (292 ml) and the mixture was heated to 120 ° C. After stirring at this temperature for 25 h, in the HPLC analysis procedure of the crude reaction mixture it was indicated that it remained <2 RAP of day. Water (500 ml) was slowly charged, maintaining the temperature <35 ° C. The suspension was cooled to 0-5 ° C and maintained at this temperature for 1 h. The crystals were collected by filtration. The filter cake was washed with water (2 x 250 ml). The solid product was dried in an oven of

10 vacuum (15-25 mm, 35-45 ° C) for an LOD <1% (w / w). The solid (79.7 g, 97.0%) (Compound F ') had an HPLC AP 99.6, 1 H NMR: (500 MHz, DMSO-d6) 8 8.45 (s, 1 H), 8.01 (s, 1H), 7.47 (d, J = 13.5 Hz, 1H), 4.37 (d, J = 13.5 Hz, 1H), 3.08 (s, 6H), 2.89 (s, 6H); LRMS (ESI) 282.08 [(M + Li) + calc. for C12H16FN5O2 282.29].

Example 5 Preparation of Compound G 'from Compound F' (Example 4)

50 g (0.177 mol) of Compound F '(prepared as in Example 10) was loaded into the apparatus of

5 hydrogenation followed by 7.25 g of platinum on carbon (0.65% Pt / CP126 catalyst, 1% wet). The reactor was inerted with nitrogen. 443.0 (g) (500 ml, Compound F 10 ml / g) of THF were loaded into the hydrogenation apparatus. Hydrogen was charged subsurfacely in the reactor, maintaining the temperature between 15-35 ° C. The reaction was determined to be complete when <1 RAP of Compound F 'remained. The THF rich stream was purged with nitrogen and then filtered through a 10! followed by a filter 1! to remove the

10 platinum catalyst. The THF-enriched stream was transferred to the crystallizer and distilled at a minimum agitation volume. 175 ml (inlet of Compound F '3-3.5 l / kg) of 4N HCl was loaded into the crystallizer. The batch was heated at 70-80 ° C with the condenser in distillation mode to distill the remaining THF. The batch was maintained at 70-80 ° C for 15 min. and samples were taken for internal process HPLC analysis. The reaction was determined to be complete when <1 RAP of Compound Fc remained. 75 ml were loaded (input of

15 Compound F '1.5-2 l / kg) of water in the batch while maintaining the temperature above 50 ° C. The batch was cooled to 0-5 ° C and filtered. The mother liquors were recycled to transfer the batch over the filter. The cake was dehydrated for 1 h. The cake was dried at 45-50 ° C under domestic vacuum at a constant LOD. The isolated yield of Compound G '· HCl was 83.3% from Compound F'. Analytical data: 1H NMR (300 MHz, d6-DMSO): 8 13.30 (s, 1H), 13.03 (sa, 1H), 8.44 (s, 2H), 7.87 (t, J = 2.6 Hz, 1H), 7.60 (d, JF-H = 4.7 Hz, 1H), 6.61 (dd, J = 2.6 Hz, JF-H = 2.0

20 Hz, 1H); 13C NMR (75 MHz, d6-DMSO) 8 148.0 (d, JF-C = 237 Hz), 144.1, 134.0, 126.2 (d, JF-C = 24 Hz), 120.8 (d, JF-C = 11 Hz), 111.5 (d, JF-C = 37 Hz), 101.7, LCMS: 152 (M + 1).

Example 6

Preparation of Compound H 'from Compound G' HCl (Alternative Procedure 1)

Compound G '· HCl salt (20.0 g, 0.107 mol), K3PO4 (23.0 g, 0.111 mol), methylsulfonyl hydrazide (18.9 g, 0.138 mol) and MeCN (500 ml) were loaded into a flask with three mouths of 1 liter. The resulting suspension was stirred at room temperature for approximately 0.5 h. Then, 2,2-dimethoxyacetaldehyde (60% in water, 24.1 g, 0.138 mol) was added and the mixture was heated at 70 ° C for a period of 20 ~ 30 min. After stirring at this temperature for an additional 2 h, the MeCN solvent was distilled off at atmospheric pressure. DMA (100 ml) was loaded in the

30 flask and the mixture was heated to 105 ° C. The batch was maintained at this temperature for 2 h and then cooled below 50 ° C. Deionized water (200 ml) was added over a period of 10 min and the resulting suspension was cooled to 0-5 ° C. The crystals were collected by filtration. The cake was washed with deionized water (400 ml), dehydrated for 1 h and dried under vacuum at 50 ° C to produce H 'as a yellow solid (17.4 g, 80% yield).

EXAMPLE 7

Preparation of Compound Ga for Use in the Preparation of Compound H 'from Compound G' (alternative procedure 2, Part I), as described in Example 14

5 Methanesulfonohydrazide, compound g. (90.85 mmol; 10.01 g) is a 500 ml three-mouth flask, followed by tetrahydrofuran (50.0 ml) and 2,2-dimethoxyacetaldehyde, compound f (99.97 mmol; 15.22 ml; 17.35 g). The mixture was stirred at room temperature and the reaction was monitored with TLC (silica, EtOAc). After 3.5 h at room temperature, ethyl acetate (2.13 mol; 250.00 ml; 217.80 g) was added. The solvent was distilled in an oil bath at 45 ° C in a vacuum of 80 ± 1 mmHg at ~ 50 ml of the white residual suspension; the

The internal temperature rose from ~ 23 ° C to ~ 34 ° C. KF of the residue was 0.463 and a crystalline suspension was obtained. Heptane (100.00 ml) was added to the suspension for ~ 0.5 h, which was stirred overnight. The suspension was filtered, the flask was washed with the mother liquor and the solid with heptane (2 x 30 ml), yielding (E) -N '- (2,2-dimethoxyethylidene) methanesulfonohydrazide as a white crystalline powder. (16.2438 g, 91.1% yield). Mp 82.4 ° C; decomposition, 123.8 ° C; 1H NMR (500 MHz, d-DMSO), 8 11.01 (s, 1H), 7.16 (d, J = 5.50 Hz, 1H), 4.74 (d, J =

15.50 Hz, 1H), 3.31 (s, 6H), 3.00 (s, 3H); 13C NMR (125 MHz, d-DMSO), 8145.3, 101.5, 53.3, 38.4; Elemental analysis, Cal for C5H12N2O4S: C, 30.60; H, 6.16; N, 14.27; S, 16.34. Found: C, 30.72; H, 6.02; N, 14.41; S, 16.08.

EXAMPLE 8

Preparation of Compound H 'from Compound G' (alternative procedure 2, Part II)

15.00 g of G (HCl salt) were neutralized with 90 ml of 1.0 N NaOH, then extracted with 200 ml of EtOAc. The EtOAc phase was washed with 2 x 100 mL of H2O, dried over MgSO4, filtered and concentrated by rotary evaporation, giving solid G '(9,872 g). 4-Fluoro-1H-pyrrolo [2,3-c] pyridin-7-amine (G ', 1.00 equiv, 65.3156 mmol; 9.8720 g), dibasic potassium phosphate (1.00 equiv; 65.3894 mmol; 11.5043 g), (E) -N '- (2,2-dimethoxyethylidene) methanesulfonohydrazide (Ga, 1.29 equiv 84.2901 mmol; 16.5400 g) and dimethylacetamide (100.00 ml )

25 in a 250 ml flask that was degassed and purged with N2. The suspension was stirred at room temperature for ~ 10 min. The suspension was gradually heated for ~ 50 min at 100 ° C and the reaction was monitored with HPLC. After 4 h, the reaction mixture was cooled to 20-22 ° C. 300 ml of H2O was added and the suspension was stirred for ~ 0.5 h. The suspension was filtered and the solid was washed with H2O (3 x 100 mL) and dried at 50 ° C under vacuum, yielding H 'as a brown solid (11.5141 g, 87% yield, 99, 2 AP).

EXAMPLE 9 Preparation of Compound L 'from Compound H' (Example 6 or 8)

Ethyl magnesium chloride (500 ml of a 2M solution in THF, 1000 mmol, 3.5 equiv.) Was added to a solution of the

5 Compound H '(285.9 mmol) in THF (2324 ml) between -5 and -10 ° C. After 1 h of stirring at -10 ° C, pyridine (11.5 ml, 143 mmol, 0.5 equiv.) Was added between -5 and -10 ° C. The mixture was cooled to between -40 and -50 ° C and methyl chloroxoxoacetate (109.5 ml, 145.9 g, 1143.6 mmol, 4 equiv.) Was added between -40 and -50 ° C. The mixture was stirred for 1 h, heated to -10 ° C and stirred for 2 h. The mixture was quenched with methanol (116 ml, 91.9 g, 2868 mmol, 10 equiv.), Followed by water (1452 g). The resulting suspension was filtered and the solids washed with water (2 x 580 ml) followed

10 methanol (1 x 580 ml). The solids were dried between 35 and 45 ° C under vacuum and a constant nitrogen flow to LOD (loss in drying) to produce 51.6 g of Compound L '(62% yield) as an off-white solid: 1H NMR (300 MHz, DMS0-d6) 8 9.03 (d, 1H, J = 1.1 Hz), 8.59 (s, 1H), 8.30 (d, 1H, J = 2.3 Hz ), 8.11 (d, 1H, J = 1.1 Hz), 3.92 (s, 3H); 13C NMR (400 MHz, DMS0-d6) 8 177.8, 163.7, 152.5 (d, J = 259 Hz), 142.3, 134.3, 131.8, 126.4 (d, J = 27.6 Hz), 125.8, 123.1, 122.6 (d, J = 20.7 Hz), 112.5, 53.1; HMS: calc. for C12H8FN5O3 [(M + H)

15 ion]: 290.0689, found: 290.0693.

EXAMPLE 10

Preparation of Compound II from Compound L '

10.0 g (0.0345 mol) of compound L ', 9.4 g (0.0415 mol, 1.2 equiv. Mol based on powers of both were charged

20 starting materials) of compound Dc, 170 ml (10 ml / g of compound L ') of THF and 5.0 ml (0.5 ml / g of compound L') of DMF in a 3-mouth Morton flask and 500 ml The KF of the mixture was measured and 2.0 mol of trimethyl orthoformate / mol of the total amount of water present in the reaction mixture was added followed by the addition of 0.53 ml (0.2 mol equiv. Of compound L ') of trifluoroacetic acid and the resulting mixture was stirred at room temperature for 0.5 h. If the KF of the mixture is not below 100 ppm, water and an amount can be added

25 1.0 equiv. additional mole of trimethyl orthoformate. When the KF is below 100 ppm, the mixture is cooled to -10 to 0 ° C. 33.9 ml (30.8 g, 2.7 mol equiv.) Of a 30% by weight solution of 97% sodium t-butoxide in THF were charged into the flask, keeping the temperature below 0 ° C. The reaction mixture was maintained at -5 at 0 ° C and followed by HPLC. It was determined that the reaction was complete when less than 1% relative area (RAP) of compound L 'remained. 1.0 ml of water (compound L '0.1 ml / g was charged, maintaining the temperature by

30 below 5 ° C. The reaction mixture was heated at 20 ° C, maintained at this temperature for 1 h and then cooled again to 0 ° C. This step degraded an impurity present in the reaction mixture. Then, 49 ml (compound L'1.9 ml / g) of water was added, keeping the temperature below 5 ° C and the resulting homogeneous solution was filtered through a Whatman No. 4 filter paper. The apparent pH of The mixture was adjusted from 6.3 to 6.8 with 51 ml of 1 N HCl. Water (160 ml, compound L'16 ml / g) was added. The resulting suspension containing the

The monohydrate H1 form of compound II was simply heated to reflux (from 75 to 80 ° C), maintained at this temperature for 0.5 h and cooled from 18 to 20 ° C for a period of 2 h. The crystals were collected by filtration. The cake was washed with 200 ml of water, followed by 50 ml of absolute ethanol, dehydrated for 1 h and

dried under vacuum at 50 to 55 ° C to produce 12.8 g (83.0%) of a white crystalline solid. m.p. 281.16, 1 H NMR (300 MHz, d6-DMSO) 8 9.02 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.45 (s, 5H), 3.35-3.80 (m, 8H), 2.52 (s, 1H). 13C NMR (300 MHz, d6-DMSO) 8 184.4, 169.6, 165.8, 152.5 (d, JF-C = 258 Hz), 141.9, 135.8, 134.4, 131 , 8, 130.1, 128.8, 127.4, 126.3 (d, JF-C = 28 HZ), 125.9 (d, JF-C = 9 Hz), 123.2, 122.2 (d, JF-C = 22 Hz), 113.4, 45.7, 41.2; HMS calc. for C22H18FN7O3 448.1533, found 448.1530.

The resulting crystals were identified as Form N-1 crystals of derivative II of 1,2,3-triazole. X-ray powder diffraction patterns calculated (simulated) and observed (experimental) of Form N1 crystals of 1,2,3-triazole derivative II are shown in Figure 5. The diffractogram shows specific peaks at interval 28 of 5-36º, including those values of 28 (CuKaI = 1.5418 Å) 5.3 ± 0.1, 8.1 ± 0.1, 9.6 ± 0.1, 16.2 ± 0.1, 17.0 ± 0.1, 19.6 ± 0.1, 20.7 ± 0.1 and 23.2 ± 0.1.

Form N-1 crystals normally show a fusion with decomposition with the onset of endothermia at approximately 279 ° C according to differential scanning calorimetry (DSC) Figure 6 and thermogravimetric analysis (TGA) (Figure 7). The TGA shows an insignificant weight loss up to about 100 ° C, a moisture sorption isotherm of crystals of Form N-1 is shown in Figure 8, which shows a water uptake of approximately 0.1% by weight in the range from about 25% RH to about 75% RH at 25 ° C.

EXAMPLE 10A

Preparation of Form N-1 of Derivative II of 1,2,3-triazole from the corresponding Form P-6

Two 10 mg samples of the P-6 form of derivative II of 1,2,3-triazole were dissolved in aqueous acetonitrile and a solvent mixture containing CH2Cl2, MeOH and acetonitrile. Transparent solutions were obtained by heating. Small fine needles appeared, they were kept in the solutions at 45 ° C for a few days and then at room temperature for the crystals to enlarge. A 10 mg sample was dissolved in 0.7 ml of acetonitrile and 0.7 ml of MeOH. A clear solution was obtained by heating. Slow evaporation of the solution provided large crystal sticks that were identified as the N-1 form of derivative II of 1,2,3-triazole.

P-6 form of derivative II of 1,2,3-triazole was obtained by crystallization of derivative II of crude 1,2,3-triazole with MeOH followed by chromatography on silica gel using hexane / AcOEbCHCl3 / MeOH.

EXAMPLE 10B

Preparation of Form N-1 of Derivative II of 1,2,3-triazole from the corresponding Form P-2

Samples of 4-10 mg of the P-2 form of 1,2,3-triazole were kept in a DSC aluminum container. This vessel was placed in the DSC 2910 cell and heated at 265 ° C to 10 ° C / min and cooled in air at RT. DSC analysis of the resulting material showed a single fusion endotherm at 275 ° C, indicative of pure Form N-1.

EXAMPLE 10C

Preparation of Form N-1 or 1,2,3-Triazole Derivative by Solvent Mediated Transformation from the corresponding Form P-2

60 mg of the P-2 form form of derivative II of 1,2,3-triazole in 3 ml of IPA was stirred for 1-2 days. The suspension was filtered and the solid residue was air dried. A white powder was obtained, the DSC analysis for it showed a single fusion endotherm at 278.8 ° C, coinciding with a pure N-1 form. His PXRD was also different from the original form.

Form P-2 was prepared by crystallization of derivative II of 1,2,3-triazole with MeOH or by crystallization of derivative II of 1,2,3-triazole with MeOH followed by chromatography on silica gel using hexane / AcOEt / CHCl3 / eOH.

EXAMPLE 11

Preparation of Derivative II of stabilized amorphous 1,2,3-Triazole / PVP (40/60 w / w) using flash evaporation

A mixture of 50 ml of acetonitrile and 50 ml of ethanol was added to a mixture of crystalline Form N-1 of derivative II of 1,2,3-triazole (0.12 g) and polyvinylpyrrolidone (PVP K-30) (0 , 18 g). The resulting mixture was heated to approximately 70 ° C to perform solubilization. The resulting solution was filtered through a 0.45 or 0.20 µm filter and the solvent was distilled using flash evaporation.

Complete amorphization was confirmed by DSC (Figure 1) and PXRD (Figure 2).

EXAMPLE 12

Preparation of Derivative II of 1,2,3-Amorphous Triazole stabilized by Spray Drying (Intermediate spray drying, SDI)

Spray drying of crystalline Form N-1 of derivative II of 1,2,3-triazole with various excipients to different compositions resulted in derivative II of amorphous 1,2,3-triazole. The following compositions were used to prepare derivative II of amorphous 1,2,3-triazole: derivative II of 20% 1,2,3-triazole / 80% polyvinylpyrrolidone K30 (PVP, w / w), derivative II of 20% 1,2,3-triazole / 80% PVP-VA (polyvinylpyrrolidone-vinyl acetate copolymer, w / w), derivative II of 40% 1,2,3-triazole / polyvinylpyrrolidone K30 at 60 % (PVP, w / w), derivative II of 40% 1,2,3-triazole / 60% PVP-VA (polyvinylpyrrolidone-vinyl acetate copolymer, w / w), derivative II of 1,2, 20% 3-triazole / 75% PVP-VA / 5% d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS). The solvents used for

Dissolving the mixture by spray drying included dichloromethane, dichloromethane / ethanol (80/20, v / v) and dichloromethane / ethanol / water (80/19/1, v / v / v).

The preferred process for preparing amorphous 1,2,3-triazole derivative II is to dissolve derivative II of 40% 1,2,3-triazole / 60% K30 PVP at 5 mg / ml in dichloromethane / ethanol / water ( 80/19/1, v / v / v). Then, the solution is spray dried to give derivative II of 40% amorphous 1,2,3-triazole / 60% PVP-K30. The details of this

15 procedures are provided in Example 12.

EXAMPLE 13

Preparation of 1,2,3-Amorphous Triazole by Spray Drying

Form N-1 of derivative II of 1,2,3-triazole (4.0 g) and PVP-K30 (6.0 g) was dissolved in 800 ml of water / ethane / dichloromethane 1/19/80 (v / v), total solids concentration: 1.25% w / v. The solution was filtered to remove the

20 foreign matter. The filtered solution was sprayed at a rate of 5% (~ 8 ml / min) with nitrogen atomization of 400 Nl / hour. The inlet temperature of the spray dryer was maintained at 100 ± 55 ° C. The outlet temperature was maintained at 65 ± 55 ° C. The resulting particles were separated into a cyclone and collected in a receiving vessel.

Interval of processing conditions used in a Buchi B-191 spray dryer:

Inlet temperature: 45-110 ° C

Outlet temperature: 35-70 ° C

Flow rate: ~ 8-15 ml / min

Solution concentration: 0.65-1.25% w / v

A typical PXRD pattern of amorphous 1,2,3-triazole derivative II prepared by spray drying in the presence of excipients is provided in Figure 3. The typical modulated DSC curve (MDSC) of derivative II of 1,2, Amorphous triazole in the presence of excipients is provided in Figure 4a (open container) and in Figure 4b (hermetically sealed container).

EXAMPLE 14

35 Preparation of amorphous 1,2,3-Triazole Derivative II, using an SD-Micro Spray Dryer

Form N-1 of derivative II of 1,2,3-triazole (16 g) and PVP Plasdon-29/32 (equivalent to K30) (24 g) was dissolved in a mixed solvent of DCM 3395.7 g (dichloromethane ) and absolute ethanol 505.2 g (100% graduation). The total solids concentration was ~ 1.02% (w / w). The solution was sprayed through a two-fluid injector (0.5 mm diameter) with atomization pressure with 0.5 bar nitrogen and a liquid flow rate of ~ 30 g / min. He

40 process gas flow rate (hot nitrogen) was adjusted to ~ 25 kg / h. The inlet temperature of the spray dryer was maintained at 70 ± 5 ° C. The outlet temperature was maintained at 45 ± 5 ° C. The resulting particles were separated in a cyclone and collected in a receiving vessel.

Additional conditions were tested using a Niro SD Micro spray punch:

Processing Conditions Interval:

45 Inlet temperature: 60-100 ºC

Outlet temperature: 40-80 ° C

Flow rate: 20-30 g / min

The concentration of the solution was maintained at approximately 1% w / w

EXAMPLE 15

Derivative II of amorphous 1,2,3-triazole Prepared in a PSD-1 spray dryer

Form N-1 of derivative II of 1,2,3-triazole (134 g) and PVP (Plasdone-29/32, 201 g) was dissolved in a premixed solvent containing absolute ethanol (100% graduation) and DCM ( 4.2 kg / 28.4 kg). The total solids concentration was ~ 1.03% (w / w). The solution was sprayed in a Niro PSD-1 spray dryer equipped with a two fluid injector (1.0 mm diameter). An in-line filter (Demicap Peplyn Plus, 0.2-10 micrometer aperture) was used (before pumping the solution to the spray nozzle) to remove any particles in the solution. Then, the filtered solution was sprayed through the nozzle of two fluids with nitrogen pressure atomization at 0.4 bar. The flow of processing gas (hot nitrogen) was adjusted to ~ 80 kg / h. The inlet temperature of the spray dryer was maintained at 110 ± 25 ° C and the outlet temperature was maintained at 65 ± 25 ° C. The feed solution flow rate was adjusted accordingly (to maintain the processing temperatures) but it was measured to be approx. 80 g / min

The resulting particles were separated in a cyclone and collected in a receiving vessel. More material was collected from the bag filter than was placed after the cyclone. The material was further dried in the oven to remove residual solvent DCM.

The batch of the same size was repeated in 3 sublots and a total of 63 1 g of spray dried intermediate were collected. The total usable yield was 62.8%. More material was collected from the filter bag, from the brushing of the drying chamber and from the containers that collect the process and start / stop residues. The total material count was added to 90%.

EXAMPLE 16

Derivative II of amorphous 1,2,3-triazole Prepared in a PSD-1 spray dryer

Form N-1 of derivative II of 1,2,3-triazole (138 g) and PVP (Plasdone-29/32, 207 g) was dissolved in a premixed solvent containing absolute ethanol (100% graduation) and DCM ( 4.4 kg / 29.3 kg). The total solids concentration was ~ 1.03%. The solution was sprayed using a Niro PSD-1 spray dryer equipped with a two-fluid nozzle (1.0 mm diameter). An in-line filter (Demicap Peplyn Plus, 0.2-10 micrometer aperture) was used (before the solution was pumped into the spray nozzle) to remove any particles in the solution. Then, the filtered solution was sprayed through a two-fluid nozzle with nitrogen atomization pressure at 0.4 bar. The processing gas flow rate (hot nitrogen) was adjusted to ~ 80 kg / h. The inlet temperature of the spray dryer was maintained at 110 ± 2 ° C and the outlet temperature was maintained at 65 ± 2 ° C. The feed solution flow rate was adjusted accordingly (to maintain the processing temperatures) but it was measured to be approx. 80 g / min The resulting particles were separated in a cyclone and collected in a receiving vessel. The material was further dried by a Niro-Aeromatic MP-1 fluid bed processor to remove residual solvent. The same size batch was repeated in 6 sublots and a total of 1130 g of spray drying intermediate were collected. The total usable yield was 54.6%. More material was collected from the filter bag, from the brushing of the drying chamber and from the containers that collect the process and start / stop residues. The total material count was 89%.

EXAMPLE 17

Studies of Crystal Shapes Prepared in Previous Examples

one.

 X-ray powder diffraction data (PXRD) was obtained with a

Bruker D8 Advance diffractometer (Karlsruhe, Germany) that was equipped with a monochrome CuKa source that operated at a 40 KV and 40 mA tube load. A divergence system, anti-dispersion and with 1.0, 1.0 and 0.1mm reception slits, respectively, were used. The sample was scanned in a locked coupled scan mode (stage size 0.05 °; scan rate 0.4 s per stage) from 5 to 40 ° 28.

2.

 X-ray powder diffraction data (PXRD) was also obtained using a manual Bruker GADDS (General Area Detector Diffraction System). The dust samples were placed in thin-walled glass capillaries 1 mm in diameter or smaller; The capillary was rotated during data collection. The sample-detector distance was 15 cm. The radiation was Cu Ka (I = 1.5418 Å). Data were collected for 3 <28 <35 ° with a sample exposure time of at least 1800 seconds.

3.

 All simulated PXRD patterns were calculated from refined atomic coordinates of crystalline structures at room temperature, using JPOWD software (JPOWD. Powder Diffraction Simulation and Structure Display. Materials Data Inc., Livermore, California, United States, 2000).

Four.

 The single crystal X-ray data was collected on a Bruker SMART 2K CCD diffractometer equipped with monochromatic graphite Cu Ka radiation, (I = 1,54056 Å). A complete data set was collected using scan mode 0 during interval 28 with a glass-to-glass distance of 4.98 cm. An empirical absorption correction used the SADABS routine associated with the diffractometer (Bruker AXS. 1998, SMART and SAINTPLUS. Detector Control and Integration Software area, Bruker AXS, Madison, Wisconsin, United States, 1998). The final unit cell parameters were determined using the complete data set.

5.

 All structures were dissolved by direct procedures and refined by the least square techniques of full matrix, using SHELX-TL (Sheldrick, GM. 1997, SHELXTL. Structure Determination Programs. Version 5.10, Bruker AXS, Madison, Wisconsin, States United.).

6.

 The atomic parameters obtained (coordinates and temperature factors) were refined through least squares of complete matrix. The reduced function in refinements was Lw (| Fo | - | Fc |) 2. R is defined as L || F | | F || / L | Fo | while Rw = [Lw (| Fo | - | Fc |) 2 / Lw | Fo | 2] 1/2 when w is an appropriate weighting function based on errors in the observed intensities. Different maps were examined at all stages of refinement. Hydrogen atoms were introduced at ideal positions with isotropic temperature factors.

7.

 The crystalline data for the N-1 form of the invention including unit cell constants, spatial group and atomic coordinates in the asymmetric unit are classified in Tables 1 and 2. A detailed account of the technique used for the analysis of a single crystal can be found in Stout &amp; Jensen, "X-Ray Structure Determination: A Practical Guide", (MacMillian, 1968).

8.

 Differential scanning calorimetry (DSC) experiments were performed on a Q1000 model from TA Instruments ™. The sample (approximately 2-6 mg) was weighed in an open aluminum container or tightly sealed container with bites, accurately recorded at one hundredth of a milligram and transferred to the DSC. The instrument was purged with nitrogen gas at 50 ml / min. The data was collected between room temperature and 300 ° C at a heating rate of 10 ° C / min. The graph was made with the endothermic peaks pointing down.

9.

 The thermogravimetric analysis (TGA) experiments were performed on a Q500 model from TA Instruments ™. The sample (approximately 10-30 mg) was placed in a platinum vessel previously tared. The sample weight was measured accurately and recorded at one thousandth of a milligram using the instrument. The oven was purged with nitrogen gas at 100 ml / min. The data was collected between room temperature and 300 ° C at a heating rate of 10 ° C / min.

10.

 The moisture sorption isotherms were collected in a VTI SGA-100 Symmetric Vapor Analyzer, using approximately 10 mg of sample. The sample was dried at 60 ° C until a loss rate of 0.0005% by weight / min was obtained for 10 minutes. The sample was tested at 25 ° C and 3 or 4, 5, 15, 25, 35, 45, 50, 65, 75, 85 and 95% RH. Balance was achieved in each HR when the speed of 0.0003% by weight / min was achieved for 35 minutes or a maximum of 600 minutes.

TABLE 1

Single Crystal data and structure refinement for Form N-1 of derivative II of 1,2,3triazole

Empirical formula

C22H18F1N7O3

Formula weight

447.43

Temperature

293 (2) K

Wavelength

1.54178 A

Crystal system, space group

Monoclinic, C2 / c

Unit cell dimensions

a = 39,2481 (14) Å a = 90 °

b = 5.5577 (2) Å

1 = 122,399 (4) °

c = 21.8072 (10) Å

Y = 90 °

Volume

4016.3 (3) Å3

Z, calculated density

8, 1,480 Kg / m3

Absorption coefficient

0.918 mm-1

Crystal size

0.25 x 0.05 x 0.02 mm

8 interval for data collection

2.67 at 60.40 °

Fractional atomic coordinates are classified for Form N-1 of derivative II of 1,2,3-triazole in Table 2.

TABLE 2

Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103). U (equiv.) Are defined as one third of the orthogonalized Uij tensor trace

x

Y z U (equiv.)

O (1)

5444 (1) -432 (9) 3445 (2) 67 (1)

O (2)

5456 (1) 993 (7) 4862 (2) 56 (1)

O (3)

3827 (1) 6741 (12) 1978 (3) 114 (2)

N (1)

6607 (1) 2448 (8) 4493 (2) 45 (1)

N (2)

6700 (1) 7748 (8) 5605 (3) 50 (1)

N (3)

7232 (1) 6125 (8) 5563 (2) 42 (1)

N (4)

7408 (1) 4199 (8) 5474 (3) 56 (1)

N (5)

7788 (1) 4753 (9) 5745 (3) 55 (1)

N (6)

4959 (2) 2636 (10) 3810 (3) 64 (2)

N (7)

4293 (2) 5667 (13) 3089 (3) 96 (2)

F (1)

5666 (1) 6028 (6) 4842 (2) 65 (1)

(Continuation)

Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103). U (equiv.) Is defined as one third of the orthogonalized Uij tensor trace

C (1)

6257 (2) 1249 (10) 4093 (3) 42 (1)

C (2)

6558 (2) 4283 (9) 4866 (3) 39 (1)

C (3)

6817 (2) 6046 (10) 5328 (3) 44 (1)

C (4)

6311 (2) 7685 (11) 5420 (3) 54 (2)

C (5)

6048 (2) 5980 (10) 4996 (3) 46 (2)

C (6)

6159 (2) 4181 (10) 4692 (3) 41 (1)

C (7)

5973 (2) 2191 (10) 4214 (3) 41 (1)

C (8)

7846 (2) 7025 (12) 5999 (3) 58 (2)

C (9)

7499 (2) 7938 (11) 5889 (3) 56 (2)

C (10)

5578 (2) 1128 (11) 3916 (3) 47 (2)

C (11)

5323 (2) 1688 (10) 4246 (3) 47 (2)

C (12)

4820 (3) 3682 (18) 3094 (5) 117 (4)

C (13)

4618 (2) 5763 (19) 2945 (5) 123 (4)

C (14)

4444 (3) 4810 (20) 3842 (5) 122 (4)

C (15)

4649 (2) 2648 (14) 3988 (4) 80 (2)

C (16)

3917 (2) 6071 (12) 2578 (4) 61 (2)

C (17)

3590 (2) 5667 (11) 2728 (3) 49 (2)

C (18)

3509 (2) 7309 (12) 3101 (4) 70 (2)

C (19)

3179 (2) 6970 (15) 3168 (4) 77 (2)

C (20)

2942 (2) 5019 (18) 2868 (4) 81 (2)

C (21)

3022 (2) 3372 (14) 2494 (4) 76 (2)

C (22)

3349 (2) 3710 (12) 2431 (4) 68 (2)

H (1 N)

6827 2124 4513 70 (20)

H (1A)

6213 -24 3782 fifty

H (4A)

6221 8889 5597 65

H (8A)

8091 7845 6218 70

H (9A)

7455 9460 6010 67

H (12A)

5053 3938 3058 1401

H (12B)

4647 2519 2725 140

(Continuation)

Atomic coordinates (x 104) and equivalent isotropic displacement parameters (A2 x 103). U (equiv.) Is defined as one third of the orthogonalized Uij tensor trace

H (13A)

4503 6161 2438 148

H (13B)

4805 7033 3236 148

H (14A)

4622 6017 4187 147

H (14B)

4217 4613 3901 147

H (15A)

4456 1382 3715 96

H (15B)

4775 2283 4500 96

H (18A)

3674 8648 3309 84

H (19A)

3122 8087 3419 93

H (20A)

2722 4787 2915 97

H (21A)

2857 2035 2284 91

H (22A)

3405 2585 2182 82

Claims (4)

1. A process for preparing compound L, which has the structure which comprises subjecting compound H of the structure to a Grignard acylation reaction when acid chloride 1 it is reacted with compound H to form compound L. wherein the Grignard acylation reaction is carried out in the presence of C2H5MgCl in an organic solvent, 210 CH3THF and an organic base, wherein the Grignard acylation reaction is performed at a temperature in the range of about -50 at about 25 ° C and wherein in compounds L and H, R2 is F, R3 is H and R18 is H or alkyl. 2. A procedure for preparing a compound IIA having the structure which comprises reacting compound L, which is prepared by the process according to Claim 1, of the structure with a compound of the structure wherein A is selected from the group consisting of C1-6 alkoxy, aryl and heteroaryl; wherein said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, Benzofuranyl, benzothienyl, benzoimidazolyl and benzothiazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl; Y each of R9, R10, R11, R12, R13, R14, R15 and R16 is independently H or (C1-6) alkyl which may be optionally substituted with 1 to 3 the same or different halogens; 15 in the presence of an organometallic base to form compound IIA, wherein the reaction is carried out at a temperature in the range of about -20 to about 50 ° C and where in compounds IIA and L, R2 is F, R3 is H and R18 is H or alkyl. 3. A process for preparing compound IIA having the structure wherein A is selected from C1-6 alkoxy, aryl and heteroaryl; wherein aryl is phenyl or naphthyl; the heteroaryl is selected from pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoimidazolyl; and the aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from amino, nitro, cyano, hydroxy, C1-6 alkoxy, -C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl; R18 is H or alkyl; R2 and R3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR56, XR57, C (O) R7, C (O) NR55R56, B, D and E; B is selected from the group consisting of -C (= NR46) (R47), C (O) NR40R41, aryl, heteroaryl, heteroalicyclic, S (O) 2R8, C (O) R7, XR8a, alkyl (C1-6 ) -NR40R41, (C1-6) alkyl -COOR8b; wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group F; wherein the aryl is naphthyl or substituted phenyl; wherein heteroaryl a mono or bicyclic system containing 3 to 7 ring atoms for a monocyclic system and up to 12 atoms in a condensed bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is a 3 to 7 membered monocyclic ring that may contain 1 to 2 heteroatoms in the ring structure and that may be fused to a benzene or pyridine ring; D is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are optionally substituted with one to three same or different halogens or one to three same or different substituents selected from the group consisting of C (O) NR55R56 , hydroxy, cyano and XR57; X is selected from the group consisting of NH, NCH3 O and S; E is selected from the group consisting of (C1-6) alkyl and (C2-6) alkenyl; wherein said (C1-6) alkyl and (C2-6) alkenyl are independently optionally substituted with a member selected from the group consisting of phenyl, heteroaryl, SMe, SPh, -C (O) NR56R57, C (O) R57, SO2-C1-6 alkyl and SO2Ph, wherein heteroaryl is a monocyclic system containing 3 to 7 ring atoms, including 1 to 4 heteroatoms; F is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, thioalkoxy (C1-6), cyano, halogen , nitro, -C (O) R57, benzyl, -NR42C (O) -alkyl (C1-6), NR42C (O) -cycloalkyl (C3-6), -NR42C (O) -aryl, -NR42C (O) -heteroaryl, -NR42C (O) -heteroalicyclic, a cyclic N-lactam of 4, 5 or 6-membered ring, -NR42S (O) 2-alkyl (C1-6), -NR42S (O) 2-cycloalkyl (C3 -6), -NR42S (O) 2-aryl, NR42S (O) -heteroaryl, -NR42S (O) 2-heteroalicyclic, S (O) 2-C 1-6 alkyl, S (O) 2-aryl, -S (O) 2 NR42R43, NR42R43, C 1-6 alkyl-C (O) NR42R43, C (O) NR42R43, NHC ( O) NR42R43, OC (O) NR42R43, NHC (O) OR54, alkyl (C1-6) -NR42R43, COOR54 and alkyl (C1-6) -COOR54; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, (C1-6) alkoxy and aryloxy optionally are substituted with one to nine equal or different halogens or one to five substituents same or different selected from group G; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; G is selected from the group consisting of (C1-6) alkyl, (C3-7) cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, (C1-6) alkoxy, aryloxy, cyano, halogen, nitro, -C (O) R57, benzyl, -NR48C (O) (C1-6) alkyl, -NR48C (O) -cycloalkyl ( C3-3), -NR48C (O) -aryl, -NR48C (O) -heteroaryl, -NR48C (O) -heteroalicyclic, a 4, 5 or 6-membered cyclic ring N-lactam, -NR48S (O) 2 -C1-6 alkyl, -NR48S (O) 2-cycloalkyl (C3-6), NR48S (O) 2-aryl, -NR48S (O) 2-heteroaryl, -NR48S (O) 2-heteroalicyclic, sulfinyl, sulfonyl, sulfonamide, NR48R49, (C1-6) C (O) NR48R49, C (O) NR48R49, NHC (O) NR48R49, OC (O) NR48R49, NHC (O) OR54, (C1-6) -NR48R49 COOR54 alkyl and (C1-) alkyl 6) -COOR54; in which aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 7 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R7 is selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein said aryl, heteroaryl, and heteroalicyclic are optionally substituted with one to three same or different halogens or with one to three same or different substituents selected from the group F; wherein for R7, R8, R8a, R8b aryl is phenyl; heteroaryl a mono or bicyclic system containing 3 to 7 ring atoms for monocyclic systems and up to 10 atoms in a bicyclic system, including 1 to 4 heteroatoms; wherein heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R8 is selected from the group consisting of hydrogen, (C1-6) alkyl, cycloalkyl (C3-7), alkenyl (C2-6), cycloalkenyl (C3-7), alkynyl (C2-6), aryl, heteroaryl and heteroalicyclic; wherein said (C1-6) alkyl, (C3-7) cycloalkyl, (C2-6) alkenyl, (C3-7) cycloalkenyl, (C2-6) alkynyl, aryl, heteroaryl and heteroalicyclic optionally is substituted with one to six equal or different halogens or one to five equal substituents

or different selected from group F;

R8a is a member selected from the group consisting of aryl, heteroaryl and heteroalicyclic; wherein each member is independently optionally substituted with one to six same or different halogens

or from one to five identical or different substituents selected from the group F;

R8b is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl; R40 and R41 are independently selected from the group consisting of

(to)

 hydrogen;

(b)

 (C1-6) alkyl or (C3-7) cycloalkyl substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; Y

(C)

 (C1-6) alkoxy, aryl, heteroaryl or heteroalicyclic; or R40 and R41 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; Y

wherein said aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two same or different substituents selected from the group F; wherein for R40 and R41 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; with the proviso that when B is C (O) NR40R41, at least one of R40 and R41 is not selected from groups (a) or (b); R42  and R43 are independently selected from the group consisting of hydrogen, (C1-6) alkyl, allyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic; or R42 and R43 taken together with the nitrogen to which they are attached form a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, 4-NMe piperazine, piperidine, azepine and morpholine; and wherein said (C1-6) alkyl, (C1-6) alkoxy, (C3-7) cycloalkyl, aryl, heteroaryl and heteroalicyclic are optionally substituted with one to three same or different halogens or one to two equal substituents or different selected from group G; wherein for R42 and R43 aryl is phenyl; heteroaryl is a monocyclic system that contains 3 to 6 ring atoms, including 1 to 4 heteroatoms; heteroalicyclic is a member selected from the group consisting of aziridine, azetidine, pyrrolidine, piperazine, piperidine, tetrahydrofuran, tetrahydropyran, azepine and morpholine; R46 is selected from the group consisting of H, OR57, and NR55R56; R47 is selected from the group consisting of H, amino, halogen, phenyl and (C1-6) alkyl; R48 and R49 are independently selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl; R54 is selected from the group consisting of hydrogen and (C1-6) alkyl; R54 'is (C1-6) alkyl; R55 is selected from the group consisting of hydrogen and (C1-6) alkyl; R56 is independently selected from the group consisting of hydrogen and (C1-6) alkyl; and R57 is selected from the group consisting of hydrogen, (C1-6) alkyl and phenyl, wherein A is selected from the group consisting of C1-6 alkoxy, aryl and heteroaryl; in which said aryl is phenyl or naphthyl; said heteroaryl is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiezolyl, benzoimidazolyl, benzoimidazolyl, benzoimidazolyl, benzoimidazolyl; and said aryl or heteroaryl is optionally substituted with one or two of the same or different members selected from the group consisting of amino, nitro, cyano, hydroxy, C1-6 alkoxy,

-

C (O) NH2, C1-6 alkyl, -NHC (O) CH3, halogen and trifluoromethyl; Y

10 each of R9, R10, R11, R12, R13, R14, R15 and R16 are independently H or (C1-6) alkyl which may be optionally substituted with 1 to 3 same or different halogens; which comprises subjecting a compound H as defined in Claim 1 of the structure to a Grignard acylation reaction, in which the acid chloride 1 it is reacted with compound H to form compound L and reacting compound L with a compound Da of the structure 20 in the presence of an organometallic base to form a compound IIA. 4. The process as defined in claim 3, wherein the Grignard acylation reaction is carried out in the presence of C2H5MgCl in an organic solvent, 2-CH3THF and an organic base, wherein the Grignard acylation reaction is carried out at a temperature in the range of about 40 to about -50 ° C, wherein in compounds IIA, L and H, R2 is F, and R3 is H and wherein the reaction of compound L and compound Da is carried out at a temperature in the range of about -5 to about 5 ° C.